1. Field of the Invention
Acne vulgaris (hereafter referred to as "acne") is a dermatological disorder which commonly affects preadolescents, adolescents, and young adults. The principal clinical manifestation of the disease is the occurrence of numerous cutaneous lesions which involve the pilosebaceous follicles on the face, shoulders, chest or back. While there are a variety of lesions such as comedones, papules, pustules, and cysts associated with acne, the primary and predominant lesion which affects the pilosebaceous follicle is the comedo.
The etiology of acne is yet unknown, although some aspects of the pathogenesis of the disease, specifically the formation of comedones, have been clarified. The normal pilosebaceous follicle includes a follicular canal which is open at one end to the surface of the skin through a follicular orifice and which terminates at its other end in a cul de sac in the dermal layer of the skin. At the base of such cul de sac is a vellus hair follicle. Surrounding the neck and the cul de sac end of the follicular canal are one or more multiacinar holocrine sebaceous glands which connect with the lumen of the follicular canal by means of glandular ducts. The acini of the glands have a peripheral layer of highly proliferating undifferentiated basal cells. As these basal cells are displaced from the periphery to the center of the acini by the proliferation of other basal cells, they mature and differentiate into lipid-producing cells. These cells continue to produce a variety of lipids and to store such lipids in their cytoplasm until they eventually rupture. The lipid contents and the cellular debris of such cells forms the secretion of the sebaceous glands known as sebum. In the normal state, the sebum is expelled through the glandular ducts and the follicular canal to the surface of the skin. In acne, the normal function of the pilosebaceous follicle is disrupted by an unexplained accumulation of lipid and keratinous material in the middle of the follicular canal, which accumulation ultimately becomes a comedo. As more lipid and keratinous material are deposited on the comedo, the follicular canal begins to distend and the sebaceous glands start to atrophy. Eventually the sebaceous glands are replaced by undifferentiated epithelial cells which surround the comedo. If the comedo is exposed to the surface of the skin and involves the follicular orifice, it is classified as "open"; otherwise, it is referred to as "closed". Open comedones generally are not inflammatory while closed comedones may evolve into inflamed pustules, papules, or cysts.
Therapeutic regimens for acne involve local and systemic therapies, although the former is indicated in the vast majority of cases. Closed comedones generally are excised by local surgery. Open comedones, on the other hand, currently are treated by topical application of a variety of chemical agents which include, in the main, sulfur, resorcinol, salicylic acid, benzoyl peroxide, Vleminckx's solution (comprising sulfur, calcium polysulfide, and calcium thiosulfate), or retinoic acid (vitamin A acid). All the foregoing topical agents are known as "peeling" or "drying" agents which are believed to exert their therapeutic effect by causing erythema, irritation, and desquamation of the skin to expel comedones. The therapeutic efficacy of these agents, however, is rather variable, and their utility is limited because of the irritation caused by their application.
For further details pertaining to the field, the following review article is recommended -- J. S. Strauss, "Diseases of Sebaceous Glands", in: Dermatology in General Medicine, T. B. Fitzpatrick et al., Editors, New York, McGraw-Hill and Co., 1971, pp. 353-375.
2. Description of the Prior Art
M. T. Maynard (Arch. Dermatol. Syphilo., 42: 846 [1941]) and J. V. Straumford (Northwest Med., 42: 219 [1943]) have reported a systemic regimen for the treatment of acne which involves oral large doses of retinol (also known as vitamin A.sub.1 or axerophthol) over a prolonged period of time. The results reported by Maynard and Straumford, however, have been disputed and the efficacy of systemic therapy of acne utilizing retinol has been challenged by other investigators: J. A. Anderson et al. (Brit. Med. J., 2: 294 [1963]); F. W. Lynch et al. (Arch. Derm., 55: 355 [1947]); and G. H. Mitchell et al. (Arch. Derm., 64: 428 [1951]).
Oral administration of retinol, however, appears to have effectiveness in the management of certain hyperkeratotic skin diseases such as Darier's disease (Z. A. Leitner et al., Lancet, 251: 262 [1946]), Devergie's disease (A. L. Weiner et al., Arch. Dermatol. Syphilol., 48: 288 [1943]), and ichthyosis (J. P. Fisher, Arch. Dermatol. Syphilol., 199: 459 [1955]).
Successful topical treatment of psoriasis and ichthyosis utilizing retinoic acid (also known as vitamin A acid) has been reported by P. Von Beer (Dermatologica, 124: 192 [1962]), C. Stuttgen (Dermatologica, 124: 65 [1962]), and P. Frost et al. (Clin. Res., 16: 255 [1965]). Although Von Beer and Stuttgen attempted topical treatment of acne utilizing retinoic acid, the results were equivocal.
A. M. Kligman et al. (Arch. Derm., 99: 469 [1969]) have demonstrated effective topical treatment of open and closed comedones associated with acne by use of 0.1% solutions of retinoic acid. Kligman et al. attribute the effectiveness of the retinoic acid to its irritating properties and hence its "peeling" ability. See also the disclosure by A. M. Kligman in U.S. Pat. No. 3,729,568 (Apr. 24, 1973).
Cosmetic compositions comprising retinoic acid or esters thereof together with other ingredients are described in British Pat. No. 906,000 (Sept. 19, 1962). These compositions are not intended for the treatment of acne but rather for cosmetic control of normal keratinization of the skin which may occur after exposure to unfavorable climatic conditions.
Compositions containing resorcinol, vitamin A or its derivatives and a polyalkylene glycol for use in the treatment of acne are disclosed in British Pat. No. 901,659 (July 25, 1962). According to the specification of this patent, the resorcinol prevents the worsening of the acne by vitamin A (or its derivatives) during the early stages of therapy and the polyalkylene glycol prevents the irritation caused by the resorcinol.